Genomic spectrum of actionable alterations in serial cell free DNA (cfDNA) analysis of patients with metastatic breast cancer

We aimed to study the incidence and genomic spectrum of actionable alterations (AA) detected in serial cfDNA collections from patients with metastatic breast cancer (MBC). Patients with MBC who underwent plasma-based cfDNA testing (Guardant360®) between 2015 and 2021 at an academic institution were included. For patients with serial draws, new pathogenic alterations in each draw were classified as actionable alterations (AA) if they met ESCAT I or II criteria of the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). A total of 344 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) MBC, 95 patients with triple-negative (TN) MBC and 42 patients with HER2-positive (HER2 + ) MBC had a baseline (BL) cfDNA draw. Of these, 139 HR+/HER2-, 33 TN and 13 HER2+ patients underwent subsequent cfDNA draws. In the HR+/HER2- cohort, the proportion of patients with new AA decreased from 63% at BL to 27–33% in the 2nd-4th draws (p < 0.0001). While some of the new AA in subsequent draws from patients with HR+/HER2- MBC were new actionable variants in the same genes that were known to be altered in previous draws, 10-24% of patients had new AA in previously unaltered genes. The incidence of new AA also decreased with subsequent draws in the TN and HER2+ cohorts (TN: 25% to 0–9%, HER2 + : 38% to 14–15%). While the incidence of new AA in serial cfDNA decreased with subsequent draws across all MBC subtypes, new alterations with a potential impact on treatment selection continued to emerge, particularly for patients with HR+/HER2- MBC.


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